The need for harmonisation and innovation of neuropsychological assessment in neurodegenerative dementias in Europe: consensus document of the Joint Program for Neurodegenerative Diseases Working Group
Costa et al. Alzheimer's Research & Therapy
The need for harmonisation and innovation of neuropsychological assessment in neurodegenerative dementias in Europe: consensus document of the Joint Program for Neurodegenerative Diseases Working Group
Alberto Costa 0 1 3 4
Thomas Bak 2 4
Paolo Caffarra 4
Carlo Caltagirone 0 4 18
Mathieu Ceccaldi 4 16 17
Fabienne Collette 4 19 20
Sebastian Crutch 4 15
Sergio Della Sala 0 4
Jean François Démonet 4 12
Bruno Dubois 4 13
Emrah Duzel 4 10 15
Peter Nestor 4 10
Sokratis G. Papageorgiou 4 11
Eric Salmon 4 8 19
Sietske Sikkes 4 9
Pietro Tiraboschi 4 6
Wiesje M. van der Flier 4 9
Pieter Jelle Visser 4 7
Stefano F. Cappa 4 5 14
0 IRCCS Fondazione Santa Lucia , via Ardeatina 354, Rome , Italy
1 Niccolò Cusano University , via Don Carlo Gnocchi, 3, Rome , Italy
2 University of Edinburgh , 7 George Square, EH8 9JZ Edinburgh, Scotland , UK
3 Niccolò Cusano University , via Don Carlo Gnocchi, 3, Rome , Italy
4 Parma , Via Gramsci, 14, Parma , Italy
5 IUSS Pavia , Piazza della Vittoria 15, 27100 Pavia , Italy
6 Fondazione IRCCS Istituto Neurologico Carlo Besta , Via Giovanni Celoria, 11, Milan , Italy
7 Maastricht University Medical Centre , Dr. Tanslaan 12, Maastricht , The Netherlands
8 University Hospital of Liege , Liege , Belgium
9 Alzheimer Center/dpt Neurology, VU University Medical Center of Amsterdam , Amsterdam Neuroscience, De Boelelaan 1118, Amsterdam , The Netherlands
10 German Center for Neurodegenerative Diseases (DZNE) , Holbeinstraße 13-15, Bonn , Germany
11 Medical School, National and Kapodistrian University of Athens , Rimini street, 124 62 Haidari, Athens , Greece
12 Leenaards Memory Centre CHUV, Lausanne University Hospital , Rue du Bugnon 46, Lausanne , Switzerland
13 Institut de la Mémoire et de la Maladie d'Alzheimer (IMMA), Hôpital de la Pitié-Salpêtrière , 47-83 Boulevard de l'Hôpital, Paris , France
14 IRCCS Centro San Giovanni di Dio , via Pilastroni 4, Brescia , Italy
15 Dementia Research Centre, UCL Institute of Neurology, University College of London , Queen Square, WC1N 3BG London , UK
16 Aix Marseille University , Jardin du Pharo, 58 Boulevard Charles Livon, Marseille , France
17 University Hospital La Timone , 264 Rue Saint-Pierre, Marseille , France
18 Medicina dei sistemi, Tor Vergata University , Via Montpellier, 1, Rome , Italy
19 Cyclotron Research Centre, University of Liege , Allée du VI août, 8, Liège , Belgium
20 National Fund for Scientific Research (F.R.S-FNRS) , Quartier Agora place des Orateurs 1, Liège , Belgium
Cognitive, behavioural, and functional assessment is crucial in longitudinal studies of neurodegenerative dementias (NDD). Central issues, such as the definition of the study population (asymptomatic, at risk, or individuals with dementia), the detection of change/decline, and the assessment of relevant outcomes depend on quantitative measures of cognitive, behavioural, and functional status. Currently, we are far from having available reliable protocols and tools for the assessment of dementias in Europe. The main problems are the heterogeneity of the tools used across different European countries, the lack of standardisation of administration and scoring methods across centres, and the limited information available about the psychometric properties of many tests currently in widespread use. This situation makes it hard to compare results across studies carried out in different centres, thus hampering research progress, in particular towards the contribution to a “big data” common data set. We present here the results of a project funded by the Joint Program for Neurodegenerative Diseases (JPND) and by the Italian Ministry of Health. The project aimed at providing a consensus framework for the harmonisation of assessment tools to be applied to research in neurodegenerative disorders affecting cognition across Europe. A panel of European experts reviewed the current methods of neuropsychological assessment, identified pending issues, and made recommendations for the harmonisation of neuropsychological assessment of neurodegenerative dementias in Europe. A consensus was achieved on the general recommendations to be followed in developing procedures and tools for neuropsychological assessment, with the aim of harmonising tools and procedures to achieve more reliable data on the cognitive-behavioural examination. The results of this study should be considered as a first step to enhancing a common view and practise on NDD assessment across European countries.
Neurodegenerative dementia; Cognitive assessment; Behavioural assessment; Neuropsychological tests; Longitudinal studies; European research
The large-scale availability of cohorts at the European level
is a prerequisite for the construction of platforms for
prevention and intervention studies in neurodegenerative
dementias (NDD). A necessary step for the successful linking
of existing or planned cohort studies is the harmonisation
of clinical and biomarker data. In particular, an urgent need
is to develop a consensus on methodologies to define and
measure cognitive, behavioural, and functional status in
target populations. The role of cognitive, behavioural, and
functional assessment is crucial in longitudinal studies for
several central purposes. A quantitative assessment of
cognitive, behavioural, and functional status is needed for the
definition of the study population as asymptomatic
(individuals who present risk factors, such as ageing, but do not
manifest cognitive symptoms or signs), at risk (individuals
with mild cognitive impairment or subtle cognitive changes
not fulfilling the criteria for dementia), or individuals with
dementia (i.e. fulfilling the criteria for dementia according
to a standard definition such as cognitive impairment
impacting on social function and activities of daily living).
In addition, the same measures are used for the detection
of change/decline and for the assessment of relevant
outcomes of interventions.
Currently, we are far from having available reliable
protocols and tools for the assessment of dementias in
Europe (for a recent US perspective on this issue, see ).
The tools used are heterogeneous across different
European countries, within an individual country, and
even across different clinical and research institutes. This
situation makes it hard to compare results across studies
carried out in different centres, thus hampering research
progress, in particular towards the contribution to a “big
data” common data set.
The requirement for harmonised assessment of cognitive,
behavioural, and functional symptoms has been extensively
discussed in the field of dementia research .
Harmonisation recommendations have been proposed in the case of
vascular cognitive impairment . In the case of NDD,
surveys of assessment tools for the most common NDD,
Alzheimer’s disease (AD), used across Europe have been
published by the European AD consortium  and by a
task force of the European Federation of Neurological
Societies , demonstrating a wide variety in assessment
tools. In the last few years, the development of new
diagnostic criteria for AD [6, 7], posterior cortical atrophy ,
frontotemporal dementia - behavioural variant , and
primary progressive aphasia  all include a consideration
of recommended, disease-specific testing procedures
aiming at early diagnosis—although precise details of specific
tests are often lacking, meaning that test selection is open
to interpretation and, therefore, to potential inconsistency.
We present the results of a Working Group (WG)
supported by the Joint Program for Neurodegenerative
Diseases (JPND) and by the Italian Ministry of Health. The
aims of the WG were: 1) to provide a set of practical
recommendations for effective harmonisation procedures
allowing us to optimise the utilisation of cognitive,
behavioural, and functional data from on-going longitudinal
studies; and 2) to identify areas in which further research is
needed in order to propose harmonised innovative
assessments maximising the effectiveness of deep phenotyping,
considering in particular the possible translational impact
of cognitive neuroscience research in areas such as
memory, language, spatial orientation, action organisation,
and social cognition.
This paper is an extended version of the final report
on the JPND website (http://www.neurodegeneration
al-cohorts/call-for-working-groups/call-results). It is
structured in two main sections. In the first section, we
describe the methods. In the second section, we present
the results, in separate sub-sections for each
phenomenological dimension we reviewed, including both: 1) an
analytical discussion of current evidence; and 2)
recommendations for further developments of practice and
The flow chart shown in Fig. 1 synthetises the main steps
of the project. The project was selected in a competitive call
by the Joint Program for Neurodegenerative Diseases for
“Working Groups to Inform Cohort Studies in
Neurodegenerative Disease Research”. The recruitment of the group
members was the responsibility of the proponent, who,
during the pre-submission phase, contacted researchers
(neurologists and neuropsychologists) with a specific
competence in the diagnosis and psychometric assessment
of dementia, as documented by their scientific publications
in peer-reviewed international journals. Additional criteria
were expertise in specific sub-fields of assessment,
representation of main European research centres involved in
longitudinal studies of NDD, and availability to participate
in the working group programme (opening meeting,
6 months of at-distance work, final meeting). A total of 22
experts from eight European Union countries (Belgium,
Denmark, France, Germany, Greece, Italy, the Netherlands,
and the UK) and from Switzerland accepted the invitation
In a first workshop participants discussed the general
organisation of the workplan: reviewing the available
evidence on neuropsychological assessment of NDD in
Europe. A general distinction was made between
“global assessment”, referring to procedures used for the
initial screening of the patient’s general cognitive status,
and “detailed assessment”, encompassing target
phenotypic dimensions of dementias, intended as the main
phenomenological changes of NDD involving cognitive,
behavioural, motor, and functional domains that are
measurable by the administration of psychometric tools. These
target dimensions were defined with plenary consensus
and were identified taking into account both the clinical
manifestations that are common to all NDD and signs that
are specific to the early stages of the different syndromes.
The following target dimensions were, thus, defined as
follows: episodic memory (early involvement in the typical
form of AD), language (early impairment in primary
progressive aphasias), executive functions (early involvement
in frontotemporal dementias), visual-spatial abilities (early
impairment in posterior cortical atrophy and dementia
with Lewy bodies), behavioural symptoms (early
involvement in frontotemporal dementia – behavioural variant),
motor (early involvement in corticobasal degeneration and
in dementias with extrapyramidal symptoms), and
functional status (common to the early phases of all NDD).
Small groups encompassing three to four
researchers were then created, each dedicated to one
target dimension. The task of the small groups was to
review current methods used to investigate target
phenotypic dimensions of dementia, identify critical
issues, and provide a definite set of operational
recommendations for harmonisation purposes: identifying
un-met needs for each specific domain, taking into
account, in particular, the need for adequate
information about psychometric qualities (i.e. validity,
reliability, sensitivity, specificity). Critical issues in each area
were identified based on existing evidence as well as
the participants’ knowledge and clinical expertise.
The initial indications proposed by these small
groups were then discussed in web-based conferences
involving the whole consortium. In these conferences,
statements, procedures, and indications by the small
groups were revised.
A consensus on the available evidence and un-met
needs for each cognitive domain, identified as critical in
the assessment and monitoring of NDD, was achieved in
a final workshop, involving the entire consortium, either
by physical participation or web-conference. The
consensus on each specific issue was achieved with the
agreement of all participants.
Discussion of current evidence
The Mini Mental State Examination (MMSE) is
currently the most widely used test for cognitive screening
in clinical practice , and is mentioned by several
guidelines for the assessment of dementia and cognitive
disorders. Indeed, it shows good sensitivity and reliability
with Cronbach’s α = 0.91 . Moreover, some MMSE
items (i.e. intersecting-pentagon copy) were found to
reliably discriminate between AD and dementia with
Lewy bodies (DLB)  in an autopsy-verified
population. Nevertheless, the MMSE suffers from some
important limitations. It shows poor specificity for people with
a low educational level, who may achieve low scores
although healthy, and poor sensitivity for people with a
high educational level who can obtain high scores even
when impaired; it is highly sensitive to memory and
language disorders but not to executive functioning .
The Montreal Cognitive Assessment (MoCA) is
another brief screening measure for cognitive disorders
 consisting of a 30-point test administered in
10 min, focusing on memory, visual-spatial, executive,
and language function, and orientation to time and
place. The MoCA has the advantage of being short and
easy to administer with a good sensitivity (86%) for mild
cognitive impairment (MCI) and AD (97%) and for the
post-stroke cognitive screening . It is easily available
via a dedicated website providing free test forms in a
number of languages, including parallel versions.
The Frontal Assessment Battery (FAB)  includes
six sub-tests exploring conceptualisation, mental
flexibility, motor programming, inhibitory control, and
environmental autonomy, and is considered a reliable tool to
investigate dysexecutive symptoms in frontal-related
disorders. However, its usefulness to discriminate between
the dysexecutive profiles of different NDD is
controversial [18, 19]. In particular, the results of a study involving
individuals with mild AD and mild frontotemporal
dementia (FTD) documented that only the FAB sub-test
“go/no-go” detected significant between-group
differences, whereas performance on the other sub-tests was
quite similar. However, the authors found good
concurrent validity (i.e. significant correlation between FAB and
individual executive test scores).
Test batteries such as the AD Assessment
Scale-Cognition (ADAS-CoG) , Cambridge Cognitive
Assessment-Revised (CAMCOG-R) , and
Addenbrooke’s Cognitive Examination (ACE-R)  have
the advantage of parallel forms but the assessment of
executive functions is limited. ACE-R takes between
12 and 20 min (average 16 min) to administer (and
score) and examines attention/orientation, memory,
fluency, language, and visual-spatial functions. Future
work is needed to establish the efficacy of a brief battery
such as ACE-R in different types of dementia, even though
it has been indicated to be effective in differential
diagnosis of different forms of Parkinsonism .
The Mattis Dementia Rating Scale (MDRS)  is a
battery that assesses attention, perseveration, construction
ability, conceptualisation, and memory, and was recently
recommended by the Movement Disorder Society for the
assessment of dementia in individuals with extrapyramidal
disorders . However, administration may be
considered too lengthy for a first global screening test.
Fig. 1 The flow chart that synthetises the main steps of the project
The panel recommended a step-wise approach to be
followed in the assessment of a person in whom
dementia is suspected. As a first step, a short screening should
be performed (less than 15 min for administration). The
MMSE, MoCA, Mini-CoG , ACE or ACE-R, and the
FAB are recommended for this purpose. In the case of
clinical and psychometric evidence suggesting a
cognitive impairment, a second-level examination should be
performed. At this level, an examination by a specialist
should confirm/verify the initial diagnostic hypotheses.
For this purpose, the following tests could be used:
ADAS-Cog, CAMCOG-R, and the MDRS.
The above two steps specifically refer to the
examination of global cognitive functioning. The third step is
the in-depth examination of the neuropsychological
profile by means of tests specific to each cognitive domain.
Detailed assessment area
In this section, we report results on the phenotypic
dimensions of dementia defined by the consortium.
Recommendations for the assessment of episodic memory,
language, executive functions, visual-spatial abilities,
behavioural symptoms, and motor and functional status
are summarised in Table 1.
Episodic memory functions
Discussion of current evidence Episodic memory
disorders are a key element of the cognitive decline that
defines the clinical staging of AD. Memory disorders also
occur in many other conditions, including depression
and healthy ageing, leading to diagnostic uncertainty.
Hence, memory tests are sensitive but may not be
specific. Moreover, performance on such tests reaches a
floor very early in the disease, making them a poor
marker of disease severity and progression.
The most widely used episodic memory tests for the
identification of the amnestic syndrome of AD are based
on list learning and delayed recall. These tests include
different versions of the paired-associate learning 
and the Rey Auditory Verbal Learning tasks . It has
been proposed that tests that control for attention and
effective encoding and that can facilitate retrieval are
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particularly suitable to identify an amnestic syndrome of
the hippocampal type, typical of AD. Memory tests with
cueing, either at the bedside (5-Word Test)  or
administered by neuropsychologists (Free and Cued
Selective Reminding Test (FCSRT)) , have shown good
specificity for AD . It should be taken into account
that the above tools place heavy demands on verbal
abilities. This significantly reduces their applicability in
conditions characterised by severe language disorders
(e.g. primary progressive aphasia (PPA)). Some
neuropsychological tests with limited language demands have
been proposed. Among these, the DMS48  and the
Visual Short-Term Memory Binding Test [33, 34], which
tap long-term recognition memory and associative
processes within short-term memory, respectively, showed
good specificity for AD. They have the additional benefit
of being unaffected by healthy ageing or low education
levels. The recently proposed “5 Objects Test” has the
advantage of being unaffected by low education levels
and of having limited language demands (i.e. it requires
locations of five everyday objects, immediately after
placement, and after a brief period of time) .
A new area of research is represented by the study of
prospective memory functioning and, in particular, by
the potential contribution of prospective memory
procedures to discriminate between different pathological
Recommendations Additional information about the
sensitivity, specificity, and positive and negative predictive
value of each test proposed for clinical use in AD and in
other dementias should be achieved [37, 38]. In this regard,
it must be underlined that memory tests for dementia and
earlier stages of impairment, such as MCI, have different
requirements. The former must account for the distributed
network dysfunction of manifest dementia, the latter need
to be able to detect early and circumscribed deficits. Thus,
the sensitivity of clinical tests is likely to benefit from
incorporating the assessment of multiple memory processes,
whereas sensitivity to early AD conditions is likely to
benefit from process-specificity to the early stages of AD
pathology involving sub-sectors of the medial temporal lobe.
Other issues to consider include age effects, practice effects,
ceiling and floor effects, repeatability, ease of
administration, and correlation with biomarkers. Indeed, the
distinction between neuropathological changes in healthy ageing
and AD is disputed, making it challenging to define clear
boundaries between the two.
Among extant tools, in order to discriminate
between AD-related memory deficits and memory
disorders occurring in other NDD, at the moment it is
recommended to use more than one test. Among the
most interesting candidates for high specificity in the
very early stages of disease are the FCSRT and the
Visual Short-Term Memory Binding Test.
Discussion of current evidence Only a minority of tools
have been developed to assess language impairments either
in those NDD in which it is not a prominent feature
(typical AD) or in NDD in which language disorders represent
the main determinant of clinical presentation (PPA).
The most widely used naming test is the Boston
Naming test [39, 40]. Originally developed for stroke
aphasia, it has been adapted to wider applications with
the development of several forms (60, 30, and 15 items).
Extensive data are available about its sensitivity
(individuals with AD vs. healthy controls). Two other tests
currently used are the Graded Naming test  and the
Aachener Aphasie Test (AAT) . Important to
evidence is that picture naming tasks are sensitive to AD
 but they are less specific, as a naming disorder is a
pervasive aspect of many NDD .
Word generation tests such as phonological and
categorical fluency are widely used. However, due to the
recruitment of various cognitive processes (e.g. working
memory and executive processes) their specificity is
relatively low . The Pyramid and Palm Trees Test 
assesses non-verbal semantics, and is highly specific for
the semantic variant of PPA .
The assessment of sentence processing entails
production and comprehension. To assess production abilities,
the most used stimuli are the Cookie theft from the
Boston Diagnostic Aphasia Examination (BDAE) and the
picnic picture from the Western Aphasia Battery (WAB).
A scoring system for PPA is also available . Phrase
construction tests have been proposed as a faster,
quantitative way to assess production abilities (Northwestern
Anagram Test (NAT)) .
The most widely used tool to assess sentence
comprehension is the Token Test, originally developed as a
sensitive test for auditory comprehension in stroke
aphasia . The Test for the reception of grammar (TROG)
 or the Cycle-R  have been successfully applied
in neurodegenerative diseases to identify specific
The assessment of language disorders should also
include the evaluation of reading and spelling abilities.
In this case, The National Adult Reading Test
(NART) , or its adaptation into other languages,
is often used and also represents a valid estimation of
premorbid IQ in dementia. However, as the NART
relies on the ability to read irregular words, its
application in languages with regular orthography (e.g.
Italian and Spanish) is problematic.
Only recently there has been an interest in the
development of specific language batteries for NDD. These
include the Cambridge Semantic Memory Test  and
the Sydney Language Battery (SYDBAT) . The latter
two, however, concentrate on semantic processing rather
than an attempt to cover all aspects of language.
Furthermore, the Amsterdam-Nijmegen Everyday Language
Test (ANELT)  is an example of a test focusing on
communicative ability rather than grammatical
competence. The clinical use of extensive language
examinations is required only in the case of PPA.
Recommendations The extent of language assessment
should be closely linked to the aim of the investigation. In
general, lexical semantic processes are more affected than
syntactic or phonological processes in the early phase of
most NDD. In most settings, picture naming is the test of
choice. While many tests are in use, information about
psychometric properties, as well as parallel and
multilingual versions, is needed. In investigations of progressive
language disorders, a more comprehensive evaluation
including an analysis of extended speech production as
well as sentence-level tasks is recommended. Indeed,
impairment at the sentence level can occur also in
individuals with intact single-word processing; accordingly, in
this case, any language assessment not including sentence
processing is incomplete and potentially misleading.
Discussion of current evidence Executive disorders are
reported in the early stages of different dementia
syndromes, and their role in differential diagnosis is a matter
of debate. Indeed, under the umbrella term of “executive
functions” are included several mental operations that are
partly differentiable. Accordingly, different models of the
executive domain have been proposed . This
highlights one main difficulty in identifying suitable tests for
assessment. In this regard, reduced performance on tests
sensitive to controlled inhibition, set-shifting and
updating, is mainly associated with dorsolateral frontal
dysfunction, whereas performance on others tasks sensitive to
emotional/social cognition is mainly associated with
frontotemporal dysfunction .
As for tests sensitive to controlled inhibition, set-shifting
and working memory, Stopford et al.  showed that they
allowed detecting qualitatively distinct profiles between
individuals with FTD and with AD. In fact, impairments in
individuals with FTD reflected deficits in attention, set
shifting, and response inhibition, while impairments in
individuals with AD were influenced by information load and
working memory capacity.
Among these tests, inhibition tests are the most
sensitive to AD and, more particularly, controlled inhibition
(as, for example, in the Stroop or Hayling tasks) .
However, these tasks do not allow us to easily
distinguish between AD and the FTD-behavioural variant on a
quantitative basis ; probably a better way to
distinguish the two populations is to use qualitative measures
. Indeed, most of the clinical or conventional tests of
executive functions may be limited by their low
test/retest reliability and by reduced ecological validity .
The FAB  and the Institute of Cognitive Neurology
(INECO) frontal screening battery  are commonly
used tools for the screening of these executive functions.
However, the differential weight of their sub-items
Another applied approach to capture the variety of
executive functions is to combine different tests, and
look for the number of failed tests to assess executive
dysfunction. The GREFEX battery  includes
cognitive and behavioural tools that are standardised,
validated, and normalised for a French-speaking
population. The battery is composed of a questionnaire
(Behavioural Dysexecutive Syndrome Inventory;
Inventaire du Syndrome Dysexécutif Comportemental
(ISDC)) and seven cognitive tasks (Stroop task,
modified Six Elements Test, Trail-Making test, Adapted
version of the Brixton task, a dual-task test, verbal
fluency, and modified card sorting test). A similar
battery is the Behavioural Assessment of Dysexecutive
Syndrome (BADS)  that includes sub-tests
exploring the different dimensions of the executive domain.
Few tools are currently available to assess
emotional processes and social cognition. A classical test
investigating emotional recognition was developed by
Ekman et al.  in which subjects have to identify
basic emotions from facial expression of unknown
people presented in photographs. The Iowa Gambling
task is another popular task developed to assess
decision making abilities in situations involving
emotional activation .
False belief and Faux Pas tasks are one way to
assess theory of mind (ToM), i.e. the ability to infer the
mental state of somebody else. Although both Faux
Pas and false belief tasks have been shown to detect
a differential impairment profile in different NDD, in
particular in the comparison of individuals with
FTDbehavioural variant and individuals with AD ,
there is no consensus as to which test might be more
useful for diagnosis and for differential diagnosis of
dementia. Recently, some batteries sensitive to the
phenomenological manifestations of FTD-behavioural
variant have been proposed. Among these, the Social
and Emotional Assessment battery (SEA) ,
assessing emotion recognition and ToM abilities, has been
shown to be a promising tool for the early detection
of FTD-behavioural symptoms.
Recommendations Due to the multifaceted nature of
the executive domain, the recommendation is to include
tests assessing different executive subcomponents such
as the Stroop test (selective attention and inhibition)
, Trail Making Test (set-shifting) , Wisconsin
Card Sorting Test (set-shifting and set-maintenance)
, and verbal fluency (strategic access to lexicon) .
A comprehensive assessment of executive abilities can
be achieved by the use of standardised tests batteries
such as the BADS or the GREFEX battery.
Few standardised tests are currently available for the
specific assessment of social cognition in dementias. Among
these, promising data have been reported for the SEA.
Discussion of current evidence Dementia-related visual
impairment is often neglected. However, visual
impairments have a profound impact upon everyday life, with
previous research demonstrating that spatial perception
abilities are more strongly associated with activities of
daily living than episodic and verbal short-term memory
. Visual impairment contributes to problems as
diverse as falls and poor diet, as well as to challenging
behaviours, hallucinations, and delusions.
One limitation in many evaluations of cortical visual
function is that assessments are limited to higher order
visuoperceptual (recognition and identification of objects,
faces and scenes and their features) and visuospatial
(localisation of objects and representation of the spatial
relationship between oneself and objects in the environment
) processing without consideration of the integrity of
fundamental, basic visual processes supported by striate
and extrastriate occipital cortex (basic form, colour,
motion, and location processing). Without testing basic
visual functions, it is difficult to determine whether
higher-order object and space-perception deficits are
attributable to parietotemporal tissue loss, or in fact result
from a more fundamental de-afferentation of these areas
due to occipital lobe disease. Correct attribution of deficits
may be particularly important in clinical practice to
understand phenomenological heterogeneity in AD or to
evaluate whether there are different parietal,
occipitotemporal, and primary visual subtypes of PCA .
Conversely, there is a need to consider the impact of
cortical visual dysfunction on other domains of cognitive
test performance, particularly given the number of
neuropsychological assessments with visually mediated
instructions, stimulus presentation, or response formats. For
instance, tests of episodic memory with explicit visual
demands in encoding and/or retrieval (e.g. Rey-Osterrieth
figure copy) are obviously unsuitable for individuals with
prominent cortical visual impairment. Similarly, a majority
of tests of executive functions are partly or wholly visually
mediated. Less obvious are the more implicit visual
demands of tests such as verbal paired associate learning
that often draw on mental imagery . The clinical
experience in evaluating episodic memory function in
individuals with PCA suggests that two alternate forced
choice recognition memory tests  are particularly
suitable (although not necessarily sensitive).
Visuoperceptual and/or visuospatial impairments are
central to the diagnostic criteria of several dementias
(DLB  and corticobasal degeneration (CBD) ).
However, arguably the cardinal ‘visual dementia’ is
posterior cortical atrophy (PCA), a clinical-radiological
syndrome primarily characterised by impaired cortical
visual function with relative preservation of episodic
memory and insight .
Currently used batteries to detect deficits in early visual
processing (e.g. figure-ground discrimination) and object
and space perception include the Visual Object and Space
Perception battery (VOSP) [83, 84] and the Birmingham
Object Recognition Battery (BORB) . For a short
screening the Benton Judgement of Line Orientation [86, 87] and
the Rey-Osterrieth figure [88–90] are commonly used.
Recommendations The potential effect of basic visual
deficits on performance should be taken into account
for the choice of the tests to be used for clinical
assessment of visual-spatial disorders. With this in mind,
useful tools for the global assessment of visual-spatial
abilities are represented by the VOSP and the BORB that
allow the examination of the different visual-spatial
components. For the purpose of a short screening, the
Rey-Osterrieth figure and Benton Judgment of Line
Orientation can be reliably administered.
In order to accurately choose the different sub-tests, it
is quite important to take into consideration the patient’s
comprehension capacity. Indeed, as discussed above,
basic visual deficits could contribute to poor
performance on tasks designed to evaluate higher order visual
processes. This observation leads to the more general
issue of test validity. For example, certain VOSP
visuospatial sub-tests are better suited to individuals
with moderate typical AD (instructions for the Number
Location sub-test are more difficult to understand than
those for the Dot Counting sub-test).
Discussion of current evidence Neuropsychiatric
symptoms (NPS), otherwise defined as Behavioural and
Psychological Symptoms of Dementia (BPSD), are
present in up to 90% of all dementias  and in 35–
85% of MCI individuals . They require assisted living
or nursing facility placement and are highly clinically
relevant since severe BPSD cause significant distress on
caregivers, and affect quality of life and prognosis.
BPSD are heterogeneous and include the following:
agitation, aberrant motor behaviour, anxiety, depression, elation,
irritability, apathy, disinhibition, delusions, hallucinations,
stereotypic behaviour, sleep or appetite changes, and
abnormal sexual behaviour. The most frequent BPSD are apathy,
depression, irritability, agitation, and anxiety. There is
evidence of a stage-effect of BPSD in dementia. Affective
symptoms such as depression, anxiety, and apathy would
be prevalent in mild dementia. Psychotic signs such as
delusions, hallucinations, elation, disturbances in motor
function, and aberrant vocalisations, instead, would be more
frequent in moderate to severe dementia. A recent study in
a large population of individuals with AD reported five
distinct neuropsychiatric syndromes. The apathetic syndrome
(as a unique syndrome) was the most frequent, followed by
affective syndrome (anxiety and depression), psychomotor
(agitation, irritability, and aberrant motor behaviour),
psychotic (delusions and hallucinations), and manic
(disinhibition and euphoria) syndromes . More than 75% of
individuals with AD presented with one or more of the
syndromes. The study supports a syndromic approach, and
suggests that the clinicians need to incorporate a thorough
psychiatric examination of individuals with AD. However, it
is important to underline that around 50% of individuals
with AD, FTD, vascular dementia (VaD), and DLB show at
least four symptoms simultaneously. This makes it difficult
to individualise a cluster of symptoms that may improve
differential diagnosis accuracy.
The assessment of BPSD is performed by using
questionnaires for patients and caregivers, focused on single or
multiple signs. The Frontal Behavioural Inventory (FBI)  is
an interesting tool for the purpose of differential diagnosis
and to monitor the progression of individuals with
prominent behavioural symptoms. For AD, the first behavioural
rating scale was the BEHAVE-AD . This scale
investigates 25 behavioural symptoms and provides a rating of
caregiver’s burden. Currently, one of the most widely used
and reliable tools for the assessment of BPSD in dementia
is the Neuropsychiatric Inventory (NPI) . The NPI is a
structured interview performed with the caregiver that
assesses behavioural disorders belonging to 12 main
categories (depression, apathy, agitation, etc.), rating their
frequency, severity, and the caregiver’s distress. The NPI
was shown to be sensitive to treatment effects and able to
distinguish different NDD [97–99]. A revised version of the
NPI was recently proposed, named the Neuropsychiatric
Inventory-Clinician rating scale (NPI-C) .
Recommendations The choice of the best tool to assess
BPSD in dementia should be guided by a syndromic
approach. Accordingly, all BPSD should be investigated by
rating their severity and frequency across the different
stages of dementia that include the very early phases.
When needed for an in-depth assessment of individual
behavioural dimensions, specific ad-hoc scales should be
used. The NPI is a reliable tool for an extensive
assessment of BPSD in dementias and, thus, it is
recommended. However, for the assessment of individual
affective dimensions more specific tools such as the
Dimension Apathy Scale  and The Geriatric
Depression Scale (GDS-15)  are recommended.
Discussion of current evidence Across European
countries, not all clinicians use motor scales in their practice
with persons presenting cognitive-behavioural disorders.
This point is well outlined by results of a recent survey
(337 responses from 33 countries; presented as a poster at
the European Association of Neurology meeting in Berlin
on 20–23 June 2015 by Symonds and Bak) documenting
that 25% of neurologists and 70% of psychiatrists do not
assess motor functions regularly. Indeed, most clinicians
underestimate the frequency of motor symptoms in
memory clinics (according to the above-mentioned survey,
most clinicians believe that only 0–20% of patients in the
cognitive clinic have motor problems, while the literature
points to a much higher frequency of 30–50%).
This is problematic, since in the so-called subcortical
dementias such as, for instance, dementia associated to
Parkinson’s disease (PDD), supranuclear palsy (PSP), CBD,
Huntington disease (HD), and VaD, motor involvement is
a marker. In some cases the onset of a cognitive-motor
feature can be pathognomonic, e.g. ideomotor apraxia in
CBD, although it can also occur in AD . Systematic
studies also show that motor signs are common even in
dementia with main involvement of cortical brain areas
such as AD  and PCA .
The only commonly used scale to motor symptoms is
the Unified Parkinson’s Disease Rating Scale (UPDRS),
which has been designed specifically for Parkinson’s
disease (PD) and does not cover, therefore, many phenomena
which can be of importance in individuals with dementia
(e.g. amyotrophic features pointing to amyotrophic lateral
sclerosis (ALS)). Unfortunately, a brief motor screening
tool with standard norms and validity data that are not
disease-specific and could be used in a wide range of
diagnoses in a memory clinic is not available. Ideally, this tool
should contain items investigating areas of motor function
relevant to dementias: Parkinson symptoms (PD, DLB,
PSP, CBD, and multiple system atrophy (MSA));
amyotrophic features (ALS/FTD); cerebellar features (MSA,
alcoholism, spinocerebellar ataxea-17, etc.); and higher
order motor disorders such as praxis, motor sequencing
etc. (CBD, PCA). Recently, the Dementia Apraxia Test
(DATE)  was proposed to evaluate ideomotor apraxia
which has a sensitivity of 91% and specificity of 71%, with
a good capacity to discriminate between AD and
individuals with FTD-behavioural variant.
Recommendations A global tool that allows for the
screening of motor symptoms associated with different
dementias is not available. The use of the following
disease-specific tools that show a good validity level is
recommended: UPDRS; Unified Huntington’s Disease
Rating Scale (UHDRS); Progressive Supranuclear Palsy
Rating Scale (PSPRS); Unified Multiple System Atrophy
Rating Scale (UMSARS); and Clinical examination
according to El Escorial criteria for ALS. The development
of a brief, clinically applicable and easy-to-use
nondisease-specific motor screening tool should be a matter
of high priority. The recently developed Edinburgh
Motor Assessment (EMAS)  could fill the gap, but
it will require collection of normative data in patients
and healthy controls of different ages and a validation
against the above-mentioned established motor tests.
Promising data for the assessment of ideomotor apraxia
were reported for the DATE that could thus represent
an interesting tool to be applied for future research.
Discussion of current evidence Impairments in
instrumental activities of daily living (IADL) influence
everyday lives of patients and caregivers, and are
essential for the planning of care needs and for legal
and financial matters. As such, functional assessment
provides highly ecologically valid information. In
clinical practice, an important objective of functional
assessment is its ability to detect the impact of
cognitive impairment on everyday functioning, as this is
an important diagnostic criterion for dementia .
Additionally, the distinction between MCI and
dementia is characterised by the absence of IADL
impairments in the former, and presence of IADL
impairments in the latter . The assessment of
everyday functioning is therefore crucial both in
clinical practice and research studies. Several
longitudinal studies have demonstrated that IADL
measures in the healthy elderly are related to incident
dementia, indicating that subtle impairment in IADL
might occur earlier in the disease course .
These findings underline the relevance of a
functional assessment for the early diagnosis of dementia
. IADL assessment is also relevant for the
measurement of change over time. In particular, in
clinical trials, IADL is an outcome measure required
by the Food and Drug Administration to
demonstrate clinically relevant changes .
There is an abundance of IADL instruments,
ranging from self-report questionnaires and
informant-based questionnaires to performance-based
instruments . Different measurement methods
serve different purposes , with questionnaires
completed by the informant or study partner being
the most common assessment method. When
focusing on validity there are large differences in the
content between different instruments. Instruments
combining IADL and basic activities of daily living
(BADL) into a single instrument are less sensitive to
cognitive impairments and this might lead to an
under-estimation of functional impairment .
Within the measurement of IADL, instruments also
vary as to whether they focus on cognitive aspects of
each activity or target IADL performance. In a
systematic review, in which quality aspects and
psychometric properties of IADL instruments were rated on
a predefined scale, it was demonstrated that IADL
instruments lacked relevant information on face validity,
reliability, content, and construct validity . Other
systematic reviews supported this notion that
psychometric aspects and quality aspects received limited
attention from IADL instrument developers .
These limitations currently hamper the adequate
measurement of IADL. Most IADL questionnaires, in
particular the informant-based questionnaires, pose a
low level of burden to individuals with dementia and
their relatives and are therefore highly feasible.
Performance-based IADL instruments, on the other
hand, might be more burdensome due to time
The Lawton IADL scale  is one of the most used
and referenced traditional tools to assess instrumental
abilities in the elderly such as financial management
and telephone use. Although a good reliability for this
scale was reported, with Cronbach’s alpha up to 0.94
, it suffers from several of the limitations reported
above. Innovation of IADL was addressed in the
development of the Amsterdam IADL questionnaire
. It consists of 70 activities, based on input from
professionals, researchers, and caregivers, ensuring face
and content validity. Modern psychometric approaches
(item response theory) are applied for the scoring of
the questionnaire, enabling scoring of different
activities for different individuals on the same metric. In a
longitudinal construct validation study, the Amsterdam
IADL questionnaire was found to be sensitive to
changes over time, supporting its usefulness for
longitudinal studies .
Recommendations Quality limitations hamper
functional assessment. Although further research is needed
to investigate quality aspects of IADL instruments,
promising results have been found for several
questionnaires, including the Everyday Cognition (ECog) ,
and the Cognitive Function Instrument (CFI) , and
the Amsterdam IADL questionnaire. Therefore, the use
of these tools is recommended for research purposes.
One main point highlighted by the project is the
heterogeneity of the tests used for the assessment of the manifold
aspects of clinical manifestations of dementing conditions.
Various factors account for this heterogeneity, such as the
preference for home-made tests, the weight of local
traditions, and the context of assessment (e.g. GP practice,
memory clinic, specialist clinic, or a research centre) that is
related to the use of different tools according to the specific
aim of assessment. In this regard, one important related
issue is the “overall data fragmentation” that arises from the
use of tests with different psychometric properties. This
does not permit the merging of data from different centres
and it makes it difficult to compare published data.
The latter observation is directly related to the second
main issue of the project, i.e. the difficulty to individualise
tools with adequate levels of information about
psychometric properties. In the case of AD, for example, Logie et
al.  recently emphasised that the ideal specific
cognitive marker should not be affected by healthy ageing,
literacy level, test/re-test, and floor effects. Moreover, it
should be sensitive and specific to very early AD
manifestations, be useable in primary care, non-invasive, quick to
administer, and sensitive to daily living impairments.
Similar considerations may be applied to other NDD.
Indeed, the working group evidenced a general issue
that, across the different individual dimensions
examined here, refers to the importance of paying attention
to some crucial psychometric properties that
neuropsychological tests should ideally fulfil. As shown in
Table 2, one main point is represented by validity (i.e.
“does a test measure what it is intended for?”). Content
and construct validity should be well established.
Table 2 Recommendations for test development
Validity (i.e. does the task measure
what it is intended to measure?)
language versions for verbal tests)
Test/re-test stability; inter-rater reliability
Moreover, test administration should follow procedures
that were adopted in collecting normative data (e.g. tests
for which standardisation was individually achieved are
often administered within extensive neuropsychological
batteries). Reliability (test/re-test and inter-rater
reliability) and feasibility are other crucial prerequisites for test
administration. Indeed, although, for instance, the
invasiveness of the test (in terms of the discomfort
caused to the patient) could affect patient performance,
the issue of feasibility is often underestimated.
A related crucial issue is represented by the absence of
good quality normative data (i.e. appropriate age groups
and education levels) for many neuropsychological tools.
In view of socio-cultural changes that occur in
populations over time, a related issue refers to the need to
periodically update the normative data of psychological
tests. Moreover, many of the tests used in clinical
settings were developed several decades ago, often in
fields other than NDD (developmental disorders or
stroke). There is a danger of over-simplification in
applying this knowledge to NDD, where patterns of neuronal
loss are often incompletely understood and by far more
complex than the focal lesion models. These
observations suggest particular caution in comparing data
from studies using different tools with relatively dated
In conclusion, it is at the moment impossible to
individualise reliable and feasible protocols and tools
common to European research centres working in the
field of NDD. The panel recommended psychometric
tests that should be used with the aim of harmonising
neuropsychological research (Table 1) according to a
two-fold strategy. A first step to be followed is the
achievement of a minimal data set on the proposed
tools in order to reach two milestones: updated
normative data and updated validity data. A second step
could be the building of a common database by
sharing collected data following a “big data approach”. In
order to link data from different cohorts, z scores for
every test should be made available. For instance, to
improve research in multicentre studies, z scores
based on normative data of cognitively normal
subjects could be calculated . These z scores
could be pooled across different cognitive measures
also allowing the computation of related composite
scores. In this regard, the working group agrees on
the opportunity to correctly identify tests taking into
account a two-step model. First, tests to be applied
for short global screening of cognitive abilities that
are used to achieve general evaluation on the subject’s
mental functioning, allowing the diagnosis of
cognitive impairment. Second, tests with high predictive
value should be recommended for the diagnosis in
the very early stages of NDD, and a set of tests to be
used for the purpose of differential diagnosis through
the assessment of the neuropsychological profile
needs to be defined.
This project allowed us to identify some key points to
improve clinical research in the field of dementias. Sets
of indications are given to harmonise tools and
procedures to achieve more reliable data on the
cognitivebehavioural examination. In this regard, the results of
this study should be considered as a starting point to
enhance a common view and practice on NDD
assessment across European countries.
As it is clear from the above discussion, the possibility
to provide firm recommendations to improve
neuropsychological research in dementia syndromes suffers
from the current limitations of the tools and procedures
available. Nevertheless, an agreement was achieved on a
list of the most adequate tools and procedures to be used
for each target area according to the available evidence
(see Table 1). Here, we also identified un-met needs for
each specific domain (see Table 1) and practical
requirements of the current methods and tools of assessment,
based on existing evidence and project participants’
expertise and clinical practice. In this regard, the
consortium points out one clear indication on the usefulness to
focus further research on those instruments that reveal
potentially adequate psychometric properties for the early
assessment and differential diagnosis in NDD.
The enormous progress of cognitive neurosciences in
the last decades, resulting in novel, translational relevant
information about the organisation of cognitive functions
in the normal brain, has been exploited only to a very
limited extent in proposing new measures with increased
sensitivity and specificity to early stages of neurodegenerative
diseases. In this vein, the need for harmonisation of tools
and procedures should not hamper the possibility to
implement innovative ideas. New proposals should be shared
among the scientific community to explore the possibility
of large-scale validation and standardisation studies at the
AAT: Aachener Aphasie Test; ACE-R: Addenbrooke’s Cognitive Examination;
AD: Alzheimer’s disease; ADAS-CoG: Alzheimer’s Disease Assessment
Scale-Cognition; ADL: Basic activities of daily living; ALS: Amyotrophic
lateral sclerosis; ANELT: Amsterdam-Nijmegen Everyday Language Test;
BADL: basic activities of daily living; BADS: Behavioral Assessment of
Dysexecutive Syndrome; BDAE: Boston Diagnostic Aphasia Examination;
BORB: Birmingham Object Recognition Battery; BPSD: Behavioural and
Psychological Symptoms of Dementia; CAMCOG-R: Cambridge Cognitive
Assessment-Revised; CBD: Corticobasal degeneration; CFI: Cognitive
Function Instrument; DATE: Dementia Apraxia Test; DLB: Dementia with
Lewy bodies; ECogn: Everyday Cognition; EMAS: Edinburgh Motor
Assessment; FAB: Frontal Assessment Battery; FBI: Frontal Behavioural Inventory;
FCSRT: Free and Cued Selective Reminding Test; FTD: Frontotemporal dementia;
GDS-15: Geriatric Depression Scale; HD: Huntington disease; IADL: Instrumental
activities of daily living; INECO: Institute of Cognitive Neurology; ISDC: Inventaire
du Syndrome Dysexécutif Comportemental; JPND: Joint Program for
Neurodegenerative Diseases; MCI: Mild cognitive impairment; MDRS: Mattis
Dementia Rating Scale; MMSE: Mini Mental State Examination; MoCA: Montreal
Cognitive Assessment; MSA: Multiple system atrophy; NART: National Adult
Reading Test; NAT: Northwestern Anagram Test; NDD: Neurodegenerative
dementias; NPI: Neuropsychiatric Inventory; NPI-C: Neuropsychiatric
InventoryClinician; NPS: Neuropsychiatric symptoms; PCA: Posterior cortical atrophy;
PD: Parkinson’s disease; PDD: Parkinson’s disease dementia; PPA: Primary
progressive aphasia; PSP: Supranuclear palsy; PSPRS: Progressive Supranuclear
Palsy Rating Scale; SEA: Social and Emotional Assessment battery; SYDBAT: Sydney
Language Battery; ToM: Theory of mind; TROG: Test for the reception of grammar;
UHDRS: Unified Huntington’s Disease Rating Scale; UMSARS: Unified Multiple
System Atrophy Rating Scale; UPDRS: Unified Parkinson’s Disease Rating Scale;
VaD: Vascular dementia; VOSP: Visual Object and Space Perception battery;
WAB: Western Aphasia Battery; WG: Working Group
AC and SFC: involved in conception and design of the study and in drafting
and revising the manuscript and revising critically. TB, PC, CC, MC, FC, SC, SDS,
JFD, BD, ED, PN, SGP, ES, SS, PT, WMF and PJV: made substantial contributions
to conception and design of the study and revised the manuscript critically. All
authors read and approved the final manuscript.
The authors declare that they have no competing interests.
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